Abstract

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

Original languageEnglish (US)
Pages (from-to)321-337.e10
JournalCell
Volume173
Issue number2
DOIs
StatePublished - Apr 5 2018

Fingerprint

Atlases
Tumors
Genes
Genome
Neoplasms
Cells
Catenins
Cell growth
Phosphatidylinositol 3-Kinases
Gene expression
Fusion reactions
Gene Fusion
Apoptosis
DNA Methylation
Cell Cycle Checkpoints
Messenger RNA
Cell Cycle
Pharmaceutical Preparations

Keywords

  • cancer genome atlas
  • cancer genomics
  • combination therapy
  • pan-cancer
  • PanCanAtlas
  • precision oncology
  • signaling pathways
  • TCGA
  • therapeutics
  • whole exome sequencing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The Cancer Genome Atlas Research Network (2018). Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell, 173(2), 321-337.e10. https://doi.org/10.1016/j.cell.2018.03.035

Oncogenic Signaling Pathways in The Cancer Genome Atlas. / The Cancer Genome Atlas Research Network.

In: Cell, Vol. 173, No. 2, 05.04.2018, p. 321-337.e10.

Research output: Contribution to journalArticle

The Cancer Genome Atlas Research Network 2018, 'Oncogenic Signaling Pathways in The Cancer Genome Atlas', Cell, vol. 173, no. 2, pp. 321-337.e10. https://doi.org/10.1016/j.cell.2018.03.035
The Cancer Genome Atlas Research Network. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018 Apr 5;173(2):321-337.e10. https://doi.org/10.1016/j.cell.2018.03.035
The Cancer Genome Atlas Research Network. / Oncogenic Signaling Pathways in The Cancer Genome Atlas. In: Cell. 2018 ; Vol. 173, No. 2. pp. 321-337.e10.
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